5'-nitro-indirubinoxime induces G2/M cell cycle arrest and apoptosis in human KB oral carcinoma cells.
Our previous study demonstrated that the novel indirubin derivative, 5'-nitro-indirubinoxime (5'-NIO), effectively arrested the tumor growth through the inhibition of cell proliferation and the induction of apoptosis. However, the precise molecular mechanisms underlying 5'-NIO-induced antitumor activity remain unclear. Here, we report that 5'-NIO inhibits the proliferation of human KB oral carcinoma cells via the cell cycle arrest in G2/M phase. 5'-NIO reduced the activity of Cdc2/cyclin B complex through the inhibition of the PLK1 expression. Partially, 5'-NIO also arrested cell cycle in G1/S phase via the reduction of CDK4 and cyclin D1/D3 levels by p16 and induction of the level of p21waf1. Using flow cytometry analysis, we showed that 5'-NIO-induced cell cycle arrest is followed by apoptosis. We determined further that 5'-NIO-induced apoptosis is accomplished by the mitochondria-dependent activation of the caspase cascade. Overall, these observations suggest the potential value of 5'-NIO as a candidate for a therapeutic modality for the treatment of oral cancer.
Kim
Soo-A
SA
Department of Biochemistry, Dongguk University College of Oriental Medicine, Gyeongju 780-714, Republic of Korea.
Kim
Si-Wouk
SW
Chang
Sunghoe
S
Yoon
Jung-Hoon
JH
Ahn
Sang-Gun
SG
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D056742:Cyclin D2; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D007624:KB Cells; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D000097869:Polo-Like Kinase 1
D000970:Antineoplastic Agents; D020169:Caspases; D018797:Cell Cycle Proteins; D019938:Cyclin D1; D056742:Cyclin D2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D007211:Indoles; D010091:Oximes; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1; C534713:5'-nitroindirubinoxime; C530104:CCND1 protein, human; C080336:CCND2 protein, human; C493956:CDKN1A protein, human; C495900:CDK4 protein, human